{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T09:39:25Z","timestamp":1785749965154,"version":"3.56.0"},"reference-count":42,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["1052979"],"award-info":[{"award-number":["1052979"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["1063422"],"award-info":[{"award-number":["1063422"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The Zeb2 gene encodes a transcription factor (ZEB2) that acts as an important immune mediator in mice, where it is expressed in early-activated effector CD8 T cells, and limits effector differentiation. Zeb2 homozygous knockout mice have deficits in CD8 T cells and NK cells. Mowat\u2013Wilson syndrome (MWS) is a rare genetic disease resulting from heterozygous mutations in ZEB2 causing disease by haploinsufficiency. Whether ZEB2 exhibits similar expression patterns in human CD8 T cells is unknown, and MWS patients have not been comprehensively studied to identify changes in CD8 lymphocytes and NK cells, or manifestations of immunodeficiency. By using transcriptomic assessment, we demonstrated that ZEB2 is expressed in early-activated effector CD8 T cells of healthy human volunteers following vaccinia inoculation and found evidence of a role for TGF\u00df-1\/SMAD signaling in these cells. A broad immunological assessment of six genetically diagnosed MWS patients identified two patients with a history of recurrent sinopulmonary infections, one of whom had recurrent oral candidiasis, one with lymphopenia, two with thrombocytopenia and three with detectable anti-nuclear antibodies. Immunoglobulin levels, including functional antibody responses to protein and polysaccharide vaccination, were normal. The MWS patients had a significantly lower CD8 T cell subset as % of lymphocytes, compared to healthy controls (median 16.4% vs. 25%, p = 0.0048), and resulting increased CD4:CD8 ratio (2.6 vs. 1.8; p = 0.038). CD8 T cells responded normally to mitogen stimulation in vitro and memory CD8 T cells exhibited normal proportions of subsets with important tissue-specific homing markers and cytotoxic effector molecules. There was a trend towards a decrease in the CD8 T effector memory subset (3.3% vs. 5.9%; p = 0.19). NK cell subsets were normal. This is the first evidence that ZEB2 is expressed in early-activated human effector CD8 T cells, and that haploinsufficiency of ZEB2 in MWS patients had a slight effect on immune function, skewing T cells away from CD8 differentiation. To date there is insufficient evidence to support an immunodeficiency occurring in MWS patients.<\/jats:p>","DOI":"10.3390\/ijms22105324","type":"journal-article","created":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T23:34:46Z","timestamp":1621380886000},"page":"5324","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["The Role of ZEB2 in Human CD8 T Lymphocytes: Clinical and Cellular Immune Profiling in Mowat\u2013Wilson Syndrome"],"prefix":"10.3390","volume":"22","author":[{"given":"Katie","family":"Frith","sequence":"first","affiliation":[{"name":"Sydney Children\u2019s Hospital, Randwick, NSW 2031, Australia"},{"name":"School of Women\u2019s and Children\u2019s Health, UNSW Sydney, Sydney, NSW 2052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6419-142X","authenticated-orcid":false,"given":"C. Mee Ling","family":"Munier","sequence":"additional","affiliation":[{"name":"The Kirby Institute for Infection and Immunity in Society, UNSW Sydney, Sydney, NSW 2052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5483-1083","authenticated-orcid":false,"given":"Lucy","family":"Hastings","sequence":"additional","affiliation":[{"name":"Sydney Children\u2019s Hospital, Randwick, NSW 2031, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Mowat","sequence":"additional","affiliation":[{"name":"Sydney Children\u2019s Hospital, Randwick, NSW 2031, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meredith","family":"Wilson","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Children\u2019s Hospital at Westmead, Sydney, NSW 2145, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nabila","family":"Seddiki","sequence":"additional","affiliation":[{"name":"INSERM U955 Eq16, Vaccine Research Institute and Universit\u00e9 Paris Est Cr\u00e9teil, F-94010 Cr\u00e9teil, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Macintosh","sequence":"additional","affiliation":[{"name":"Sydney Children\u2019s Hospital, Randwick, NSW 2031, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony D.","family":"Kelleher","sequence":"additional","affiliation":[{"name":"The Kirby Institute for Infection and Immunity in Society, UNSW Sydney, Sydney, NSW 2052, Australia"},{"name":"Centre for Applied Medical Research, St Vincent\u2019s Hospital, Darlinghurst, NSW 2010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Gray","sequence":"additional","affiliation":[{"name":"Sydney Children\u2019s Hospital, Randwick, NSW 2031, Australia"},{"name":"School of Women\u2019s and Children\u2019s Health, UNSW Sydney, Sydney, NSW 2052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5912-5989","authenticated-orcid":false,"given":"John James","family":"Zaunders","sequence":"additional","affiliation":[{"name":"The Kirby Institute for Infection and Immunity in Society, UNSW Sydney, Sydney, NSW 2052, Australia"},{"name":"Centre for Applied Medical Research, St Vincent\u2019s Hospital, Darlinghurst, NSW 2010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1136\/jmg.35.8.617","article-title":"Hirschsprung disease, microcephaly, mental retardation, and characteristic facial features: Delineation of a new syndrome and identification of a locus at chromosome 2q22-q23","volume":"35","author":"Mowat","year":"1998","journal-title":"J. Med. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1038\/gim.2017.221","article-title":"Phenotype and genotype of 87 patients with Mowat\u2013Wilson syndrome and recommendations for care","volume":"20","author":"Ivanovski","year":"2018","journal-title":"Genet. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1002\/ajmg.a.61557","article-title":"Mowat\u2013Wilson syndrome in a Chinese population: A case series","volume":"182","author":"Ho","year":"2020","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.ejmg.2005.01.003","article-title":"Clinical and Mutational Spectrum of Mowat\u2013Wilson Syndrome","volume":"48","author":"Zweier","year":"2005","journal-title":"Eur. J. Med. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2027","DOI":"10.1084\/jem.20150194","article-title":"Transcriptional repressor ZEB2 promotes terminal differentiation of CD8+ effector and memory T cell populations during infection","volume":"212","author":"Omilusik","year":"2015","journal-title":"J. Exp. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1038\/ni.2842","article-title":"Early specification of CD8+ T lymphocyte fates during adaptive immunity revealed by single-cell gene-expression analyses","volume":"15","author":"Arsenio","year":"2014","journal-title":"Nat. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1038\/ni.2536","article-title":"Transcriptional insights into the CD8+ T cell response to infection and memory T cell formation","volume":"14","author":"Best","year":"2013","journal-title":"Nat. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/1750-1172-9-2","article-title":"ZEB2, a new candidate gene for asplenia","volume":"9","author":"Pons","year":"2014","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e20180922","DOI":"10.1542\/peds.2018-0922","article-title":"Mowat-Wilson Syndrome Presenting With Purpura Fulminans","volume":"143","author":"Sun","year":"2019","journal-title":"Pediatrics"},{"key":"ref_10","unstructured":"Sgruletti, M., Di Cesare, K., Chini, L., Graziani, D.S., Di Matteo, G., D\u2019Agostini, C., Falvo, F., Concolino, D., Miniero, R., and Moschese, V. (2016, January 21\u201324). Hypogammaglobulinaemia in a patient with Mowat Wilson Syndrome. Proceedings of the European Society for Immunodeficiencies 17th Biennial Meeting, Barcelona, Spain."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"10151","DOI":"10.1128\/JVI.02670-05","article-title":"CD127+CCR5+CD38+++ CD4+ Th1 Effector Cells Are an Early Component of the Primary Immune Response to Vaccinia Virus and Precede Development of Interleukin-2+ Memory CD4+ T Cells","volume":"80","author":"Zaunders","year":"2006","journal-title":"J. Virol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5251","DOI":"10.1016\/j.vaccine.2016.09.009","article-title":"The primary immune response to Vaccinia virus vaccination includes cells with a distinct cytotoxic effector CD4 T-cell phenotype","volume":"34","author":"Munier","year":"2016","journal-title":"Vaccine"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.cellsig.2018.09.002","article-title":"TGF-\u03b2 receptors: In and beyond TGF-\u03b2 signaling","volume":"52","author":"Cao","year":"2018","journal-title":"Cell Signal"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/s41580-018-0080-4","article-title":"New insights into the mechanisms of epithelial\u2013mesenchymal transition and implications for cancer","volume":"20","author":"Dongre","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1084\/jem.20171352","article-title":"ZEB1, ZEB2, and the miR-200 family form a counterregulatory network to regulate CD8+ T cell fates","volume":"215","author":"Guan","year":"2018","journal-title":"J. Exp. Med."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Memon, A., and Lee, W.K. (2018). KLF10 as a Tumor Suppressor Gene and Its TGF-\u03b2 Signaling. Cancers, 10.","DOI":"10.3390\/cancers10060161"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"v2","DOI":"10.1093\/rheumatology\/ken265","article-title":"Role of PDGF in fibrotic diseases and systemic sclerosis","volume":"47","author":"Trojanowska","year":"2008","journal-title":"Rheumatology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"34181","DOI":"10.1074\/jbc.M301247200","article-title":"CRIM1 Regulates the Rate of Processing and Delivery of Bone Morphogenetic Proteins to the Cell Surface","volume":"278","author":"Wilkinson","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6889","DOI":"10.1128\/MCB.01192-08","article-title":"Transforming growth factor beta-induced Smad1\/5 phosphorylation in epithelial cells is mediated by novel receptor complexes and is essential for anchorage-independent growth","volume":"28","author":"Daly","year":"2008","journal-title":"Mol. Cell Biol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Watanabe, J., Takiyama, Y., Honjyo, J., Makino, Y., Fujita, Y., Tateno, M., and Haneda, M. (2016). Role of IGFBP7 in Diabetic Nephropathy: TGF-beta1 Induces IGFBP7 via Smad2\/4 in Human Renal Proximal Tubular Epithelial Cells. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0150897"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.pneurobio.2015.07.001","article-title":"Zeb2: A multifunctional regulator of nervous system development","volume":"132","author":"Hegarty","year":"2015","journal-title":"Prog. Neurobiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1182\/blood-2016-05-714493","article-title":"The EMT regulator ZEB2 is a novel dependency of human and murine acute myeloid leukemia","volume":"129","author":"Li","year":"2017","journal-title":"Blood"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2015","DOI":"10.1084\/jem.20150809","article-title":"Terminal NK cell maturation is controlled by concerted actions of T-bet and Zeb2 and is essential for melanoma rejection","volume":"212","author":"Goossens","year":"2015","journal-title":"J. Exp. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5620","DOI":"10.1182\/blood-2010-08-300236","article-title":"The EMT regulator Zeb2\/Sip1 is essential for murine embryonic hematopoietic stem\/progenitor cell differentiation and mobilization","volume":"117","author":"Goossens","year":"2011","journal-title":"Blood"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2041","DOI":"10.1084\/jem.20150186","article-title":"The transcription factors ZEB2 and T-bet cooperate to program cytotoxic T cell terminal differentiation in response to LCMV viral infection","volume":"212","author":"Dominguez","year":"2015","journal-title":"J. Exp. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/1750-1172-2-42","article-title":"Mowat-Wilson syndrome","volume":"2","author":"Garavelli","year":"2007","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1007\/s00383-017-4065-8","article-title":"Guidelines for the diagnosis and management of Hirschsprung-associated enterocolitis","volume":"33","author":"Gosain","year":"2017","journal-title":"Pediatr. Surg. Int."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1016\/j.jaci.2016.12.978","article-title":"Autoimmune and inflammatory manifestations occur frequently in patients with primary immunodeficiencies","volume":"140","author":"Fischer","year":"2017","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1007\/s12016-016-8564-5","article-title":"The Clinical Relevance of Anti-DFS70 Autoantibodies","volume":"52","author":"Conrad","year":"2016","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"25929","DOI":"10.1074\/jbc.273.40.25929","article-title":"Molecular cloning and characterization of TIEG2 reveals a new subfamily of transforming growth factor-beta-inducible Sp1-like zinc finger-encoding genes involved in the regulation of cell growth","volume":"273","author":"Cook","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3799","DOI":"10.1172\/JCI87041","article-title":"TGF-beta receptor maintains CD4 T helper cell identity during chronic viral infections","volume":"126","author":"Lewis","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.immuni.2009.04.020","article-title":"Opposing effects of TGF-beta and IL-15 cytokines control the number of short-lived effector CD8+ T cells","volume":"31","author":"Sanjabi","year":"2009","journal-title":"Immunity"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.immuni.2009.06.015","article-title":"Cell-intrinsic transforming growth factor-beta signaling mediates virus-specific CD8+ T cell deletion and viral persistence in vivo","volume":"31","author":"Tinoco","year":"2009","journal-title":"Immunity"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.immuni.2013.07.016","article-title":"TGF-beta cytokine signaling promotes CD8+ T cell development and low-affinity CD4+ T cell homeostasis by regulation of interleukin-7 receptor alpha expression","volume":"39","author":"Ouyang","year":"2013","journal-title":"Immunity"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.cytogfr.2014.07.012","article-title":"Exploiting differential expression of the IL-7 receptor on memory T cells to modulate immune responses","volume":"25","author":"Zaunders","year":"2014","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1735","DOI":"10.1086\/375030","article-title":"Polyclonal Proliferation and Apoptosis of CCR5+T Lymphocytes during Primary Human Immunodeficiency Virus Type 1 Infection: Regulation by Interleukin (IL)\u20132, IL-15, and Bcl-2","volume":"187","author":"Zaunders","year":"2003","journal-title":"J. Infect. Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1002\/cyto.a.22704","article-title":"Computationally efficient multidimensional analysis of complex flow cytometry data using second order polynomial histograms","volume":"89","author":"Zaunders","year":"2016","journal-title":"Cytom. Part A"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"376","DOI":"10.3389\/fimmu.2017.00376","article-title":"HIV-1 and SIV Predominantly Use CCR5 Expressed on a Precursor Population to Establish Infection in T Follicular Helper Cells","volume":"8","author":"Xu","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2827","DOI":"10.4049\/jimmunol.0803548","article-title":"High Levels of Human Antigen-Specific CD4+ T Cells in Peripheral Blood Revealed by Stimulated Coexpression of CD25 and CD134 (OX40)","volume":"183","author":"Zaunders","year":"2009","journal-title":"J. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"E29","DOI":"10.1093\/nar\/29.5.e29","article-title":"Quantitative analysis of mRNA amplification by in vitro transcription","volume":"29","author":"Baugh","year":"2001","journal-title":"Nucleic Acids Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"68","DOI":"10.4049\/jimmunol.173.1.68","article-title":"T Follicular Helper Cells Express a Distinctive Transcriptional Profile, Reflecting Their Role as Non-Th1\/Th2 Effector Cells That Provide Help for B Cells","volume":"173","author":"Chtanova","year":"2004","journal-title":"J. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1016\/j.jaci.2006.04.040","article-title":"Immune cell transcriptome datasets reveal novel leukocyte subset\u2013specific genes and genes associated with allergic processes","volume":"118","author":"Liu","year":"2006","journal-title":"J. Allergy Clin. Immunol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/10\/5324\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:03:40Z","timestamp":1760162620000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/10\/5324"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,18]]},"references-count":42,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["ijms22105324"],"URL":"https:\/\/doi.org\/10.3390\/ijms22105324","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,18]]}}}